3-Methylene cepham compounds of the formula (I) have been known as compounds since 1966 when R. B. Morine found them as a byproduct of a ring expansion reaction of penicillin sulfoxide compounds.
There were reports that those compounds could be used for preparation of 7-aminodeacetoxy cephalosporine acid and its biologically active derivatives, and also for the preparation of 3-methoxy and 3-halocephem compounds. (refer to J. A. Chem. Soc. 95,2994 (1973), J. Am. Chem. Soc. 96,4986 (1974)). 3-Bromomethyl cepham compounds described in the following formula (III) which are useful precursors for various 3-substituted cephalosporine antibiotics can be prepared by bromination of 3-methylene cepham compounds of the formula (I). ##STR3## Wherein
R is benzyl or phenoxymethyl,
R.sub.1 is benzhydryl, p-nitrobenzyl, benzyl, p-methoxybenzyl, 2,2,2-trichloroethyl, etc.
There are three known methods of preparation of 3-methylene cepham compounds of the formula (I). In the first method, according to U.S. Pat. No. 4,159,266 (1979. 6. 26) and Korea Pat. No. 80-1399 (1980. 12. 2), 3-methylene cepham sulfoxide compounds are prepared by intramolecular cyclization of penicilline sulfoxide compounds derived through the reaction of sulfinyl chloride, sulfinic acid, sulfinate ester, thiosulfinate ester, sulfinamide, and their sulfinimide derivatives with Friedel-Crafts-catalysts or a metathetic cation forming agent.
The reaction process is represented by the following reaction scheme. ##STR4##
Although this method which employs a sulfinyl chloride intermediate is now most suitable for industrialization, there is a shortcoming in that 3-methylene cepham sulfoxide compounds have to be reduced to obtain 3-methylene cepham compounds of the formula (I).
The second method employs photo-chemical cyclization through a 4-benzothiazolidine dithioazetidinone intermediate (refer to Tetrahedron letter No. 39,3425 (1977) ) and is represented by the following reaction scheme. ##STR5##
This photo-chemical method is not economical because it needs a dilution step requiring a great amount of solvent in addition, the yield of the reaction is low.
In the third method, 2-halomethylphenam compounds are prepared by the use a 4-benzothiazolidine dithioazetidinone intermediate and 3-halo-3-methylcepham compounds are prepared from 2-halomethylphenam derivatives by the use of dimethyl formamide (D.M.F). 3-halo-3-methyl cepham sulfoxide compounds are obtained by oxidation of 3-halo-3-methyl cepham compounds. Also 3-methylene cepham sulfoxide compounds are obtained by Dehydrobromination of 3-halo-3-methylcepham sulfoxide compounds. (refer to Tetrahedron letter No. 32,3001 (1973), GB 2,013,673A (1979. 8. 15), J. Org. Chem. Vol. 42, No. 17, 2887 (1977), Tetrahedron letter No. 32,2915 (1978) ). ##STR6##
But in this method, the isomerization from 2-halomethylphenam compounds into 3-halomethyl cepham compounds does not proceed completely and 2-halomethylphenam compounds remain as a byproduct. Also there are difficulties in reducing 3-methylene cepham sulfoxide compounds.